Faculty, Staff and Student Publications

Language

English

Publication Date

4-1-2024

Journal

Advanced Science

DOI

10.1002/advs.202303775

PMID

38327094

PMCID

PMC11040377

PubMedCentral® Posted Date

2-7-2024

PubMedCentral® Full Text Version

Post-print

Abstract

The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brain，and for AD and related Tauopathies, a therapeutic target.

Keywords

Animals, Humans, Mice, Alzheimer Disease, Antigens, CD, Disease Models, Animal, Lymphocyte Activation Gene 3 Protein, Neurons, tau Proteins, Tauopathies, lymphocyte‐activation gene 3, cell‐to‐cell transmission, receptor, Tau, Tau preformed fibrils

Published Open-Access

yes

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